Fig. 4: ERS-induced pyroptosis.

In tumors, the ERS-pyroptosis axis involves three core signaling pathways that interconnect ERS and pyroptosis. Activated IRE1α initiates the downstream JNK signaling pathway through its kinase domain, leading to phosphorylation and activation of transcription factors that regulate pyroptosis-related gene expression. Concurrently, its ribonuclease activity modulates mRNA stability via the RIDD pathway, altering the intracellular protein profile and further contributing to pyroptosis regulation. ERS also activates PERK, which phosphorylates eIF2α to selectively enhance ATF4 translation. Upregulated ATF4 increases CHOP expression, which in turn promotes pyroptosis by facilitating the interaction between TXNIP and NLRP3, thereby activating the NLRP3 inflammasome. Additionally, CHOP impairs mitochondrial function, causing mitochondrial damage and the release of mitochondrial components such as mitochondrial DNA, which further amplifies NLRP3 inflammasome activation and drives pyroptosis. The ATF6 pathway modulates pyroptosis indirectly by downregulating P2×7R/NLRP3 or activating sFRP2/NF-κB signaling. Proteolytic cleavage of ATF6 can also trigger caspase-4-dependent NLRP3 inflammasome activation. These collective mechanisms ultimately lead to cleavage of GSDMD and maturation and release of IL-1β/IL-18, resulting in pyroptotic cell death. Created with BioRender.com.